tbuckley/cabot-search huggingface dataset:
A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer
Authors: Sandra Kendzia, Susanne Franke, Tarek Kröhler, Nicole Golob-Schwarzl, Caroline Schweiger, Anna M. Toeglhofer, Christina Skofler, Stefan Uranitsch, Amin El-Heliebi, Julia Fuchs, Andreas Punschart, Philipp Stiegler, Marlen Keil, Jens Hoffmann, David Henderson, Hans Lehrach, Marie-Laure Yaspo, Christoph Reinhard, Reinhold Schäfer, Ulrich Keilholz, Christian Regenbrecht, Rudolf Schicho, Peter Fickert, Sigurd F. Lax, Frank Erdmann, Marcel H. Schulz, Alexandra K. Kiemer, Johannes Haybaeck, Sonja M. Kessler
Journal: Molecular Cancer (2023)

Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches.Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses.We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells.IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.
Clinical Outcomes of Intensive Inpatient Blood Pressure Management in Hospitalized Older Adults
Authors: Timothy S. Anderson, Shoshana J. Herzig, Bocheng Jing, W. John Boscardin, Kathy Fung, Edward R. Marcantonio, Michael A. Steinman
Journal: JAMA Internal Medicine (2023)

Importance Asymptomatic blood pressure (BP) elevations are common in hospitalized older adults, and widespread heterogeneity in the clinical management of elevated inpatient BPs exists. Objective To examine the association of intensive treatment of elevated inpatient BPs with in-hospital clinical outcomes of older adults hospitalized for noncardiac conditions. Design, Setting, and Participants This retrospective cohort study examined Veterans Health Administration data between October 1, 2015, and December 31, 2017, for patients aged 65 years or older hospitalized for noncardiovascular diagnoses and who experienced elevated BPs in the first 48 hours of hospitalization. Interventions Intensive BP treatment following the first 48 hours of hospitalization, defined as receipt of intravenous antihypertensives or oral classes not used prior to admission. Main Outcome and Measures The primary outcome was a composite of inpatient mortality, intensive care unit transfer, stroke, acute kidney injury, B-type natriuretic peptide elevation, and troponin elevation. Data were analyzed between October 1, 2021, and January 10, 2023, with propensity score overlap weighting used to adjust for confounding between those who did and did not receive early intensive treatment. Results Among 66 140 included patients (mean [SD] age, 74.4 [8.1] years; 97.5% male and 2.6% female; 17.4% Black, 1.7% Hispanic, and 75.9% White), 14 084 (21.3%) received intensive BP treatment in the first 48 hours of hospitalization. Patients who received early intensive treatment vs those who did not continued to receive a greater number of additional antihypertensives during the remainder of their hospitalization (mean additional doses, 6.1 [95% CI, 5.8-6.4] vs 1.6 [95% CI, 1.5-1.8], respectively). Intensive treatment was associated with a greater risk of the primary composite outcome (1220 [8.7%] vs 3570 [6.9%]; weighted odds ratio [OR], 1.28; 95% CI, 1.18-1.39), with the highest risk among patients receiving intravenous antihypertensives (weighted OR, 1.90; 95% CI, 1.65-2.19). Intensively treated patients were more likely to experience each component of the composite outcome except for stroke and mortality. Findings were consistent across subgroups stratified by age, frailty, preadmission BP, early hospitalization BP, and cardiovascular disease history. Conclusions and Relevance The study’s findings indicate that among hospitalized older adults with elevated BPs, intensive pharmacologic antihypertensive treatment was associated with a greater risk of adverse events. These findings do not support the treatment of elevated inpatient BPs without evidence of end organ damage, and they highlight the need for randomized clinical trials of inpatient BP treatment targets.
Cribriform Morular Thyroid Carcinoma – Ultimobranchial Pouch-Related? Deep Molecular Insights of a Unique Case
Authors: Matthias S Dettmer, Sandra Hürlimann, Lukas Scheuble, Erik Vassella, Aurel Perren, Corinna Wicke
Journal: Endocrine Pathology (2023)

A 44-year-old female patient with a familial adenomatous polyposis (FAP) was diagnosed with a cribriform morular thyroid carcinoma (CMTC). We observed within the very necrotic tumor a small but distinct poorly differentiated carcinomatous component. As expected, next generation sequencing of both components revealed a homozygous APC mutation and in addition, a TERT promoter mutation. A TP53 mutation was found exclusively in the CMTC part, while the poorly differentiated component showed a clonal evolution, harboring an activating PIK3CA mutation and copy number gains of BRCA2, FGF23, FGFR1, and PIK3CB-alterations which are typically seen in squamous cell carcinoma. The mutational burden in both components was low, and there was no evidence for microsatellite instability. No mutations involving the mitogen-activated protein kinase (MAPK) pathway, typically seen in papillary thyroid carcinomas, were detected. Immunohistochemically, all tumor parts were negative for thyroglobulin, providing further evidence that this entity does not belong to the follicular epithelial cell-derived thyroid carcinoma group. CD5 was negative in the poorly differentiated component, making a relation to intrathyroidal thymic carcinoma rather unlikely. However, since this marker was seen in the morules, a loss in the poorly differentiated component and a relation to the ultimobranchial body cannot be excluded either. After total thyroidectomy and radioiodine ablation, the patient was disease-free with no residual tumor burden on 2-year follow-up.
Biallelic <i>NFATC1</i> mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis
Authors: Sevgi Kostel Bal, Sarah Giuliani, Jana Block, Peter Repiscak, Christoph Hafemeister, Tala Shahin, Nurhan Kasap, Bernhard Ransmayr, Yirun Miao, Cheryl van de Wetering, Alexandra Frohne, Raul Jimenez Heredia, Michael Schuster, Samaneh Zoghi, Vanessa Hertlein, Marini Thian, Aleksandr Bykov, Royala Babayeva, Sevgi Bilgic Eltan, Elif Karakoc-Aydiner, Lisa E. Shaw, Iftekhar Chowdhury, Markku Varjosalo, Rafael J. Argüello, Matthias Farlik, Ahmet Ozen, Edgar Serfling, Loïc Dupré, Christoph Bock, Florian Halbritter, J. Thomas Hannich, Irinka Castanon, Michael J. Kraakman, Safa Baris, Kaan Boztug
Journal: Blood (2023)

The nuclear factor of activated T cells (NFAT) family of transcription factors plays central roles in adaptive immunity in murine models; however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified 3 patients who carry germ line biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses. The compound heterozygous NFATC1 variants identified in these patients caused decreased stability and reduced the binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to rescue upon genetic reconstitution. Stimulation induced early T-cell activation and proliferation responses were delayed but not lost, reaching that of healthy controls at day 7, indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells revealed that NFATc1 dysfunction rendered T cells unable to engage in glycolysis after stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by using enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost, activation responses. Indeed, we observed increased 13C-labeled palmitate incorporation into citrate, indicating higher fatty acid oxidation, and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of the consequences of loss-of-function NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, we provide evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells, alleviating delayed effector responses.
Microgels as Platforms for Antibody‐Mediated Cytokine Scavenging
Authors: Sarah Boesveld, Yonca Kittel, Yizhao Luo, Alexander Jans, Burak Oezcifci, Matthias Bartneck, Christian Preisinger, Dirk Rommel, Tamás Haraszti, Silvia P. Centeno, Arnold J. Boersma, Laura De Laporte, Christian Trautwein, Alexander J. C. Kuehne, Pavel Strnad
Journal: Advanced Healthcare Materials (2023)

Therapeutic antibodies are the key treatment option for various cytokine-mediated diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, systemic injection of these antibodies can cause side effects and suppress the immune system. Moreover, clearance of therapeutic antibodies from the blood is limiting their efficacy. Here, water-swollen microgels are produced with a size of 25 µm using droplet-based microfluidics. The microgels are functionalized with TNFα antibodies to locally scavenge the pro-inflammatory cytokine TNFα. Homogeneous distribution of TNFα-antibodies is shown throughout the microgel network and demonstrates specific antibody-antigen binding using confocal microscopy and FLIM-FRET measurements. Due to the large internal accessibility of the microgel network, its capacity to bind TNFα is extremely high. At a TNFα concentration of 2.5 µg mL
Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci
Authors: Tomas Kanholm, Uzma Rentia, Melissa Hadley, Jennifer A. Karlow, Olivia L. Cox, Noor Diab, Matthew L. Bendall, Tyson Dawson, James I. McDonald, Wenbing Xie, Keith A. Crandall, Kathleen H. Burns, Stephen B. Baylin, Hari Easwaran, Katherine B. Chiappinelli
Journal: Cancer Research (2023)

Abstract Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation. Significance: Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
Myocardial Infarction Bends the Curve of Age-Related Cognitive Decline, but How?
Authors: Eric E. Smith, Lisa C. Silbert
Journal: JAMA Neurology (2023)

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Health Insurer Strategies to Reduce Specialty Drug Spending—Copayment Adjustment and Alternative Funding Programs
Authors: Autumn D. Zuckerman, Megan P. Schneider, Stacie B. Dusetzina
Journal: JAMA Internal Medicine (2023)

This Viewpoint describes programs intended to help patients with commercial insurance that, instead, employers, health plans, and other payers use to reduce their spending on specialty drugs.
Addressing Health-Related Social Needs—Costs and Optimism
Authors: Jenifer Clapp, Alessandra Calvo-Friedman, Nichola Davis
Journal: JAMA Internal Medicine (2023)

It is well documented that health care contributes about 20% to a person’s health, while social and economic factors contribute twice as much.1 The substantial effect of social needs on health has led to increased interest in screening for and addressing social needs within health care settings.
A “Chase and Block” Strategy for Enhanced Cancer Therapy with Hypoxia‐Promoted Photodynamic Therapy and Autophagy Inhibition Based on Upconversion Nanocomposites
Authors: Qianqian Sun, Weilin Chen, Man Wang, Pan Zheng, Minghong Gao, Fengling Song, Chunxia Li
Journal: Advanced Healthcare Materials (2023)

Abstract The combination of hypoxia‐promoted photodynamic therapy (PDT) and autophagy modulation has shown strong potential in the treatment of hypoxic tumors. Here, a novel design is put forward for synergistic PDT and autophagy inhibition to amplify the effect of cancer therapy by a “chase and block” strategy. Specifically, the organic photosensitive molecule (denoted FL) is encapsulated in a hydrophobic layer between multi‐band emitted upconversion nanoparticles (UCNPs) and the amphiphilic polymer DSPE‐PEG‐COOH, allowing FL to fully exploit the luminescence spectrum of UCNPs under near‐infrared (NIR) light irradiation. The FL is specifically activated by nitroreductase in the tumor microenvironment (TME), enabling hypoxia‐promoted PDT and thus performing a "chase" strategy for cancer therapy. Additionally, the nanosystem is combined with an autophagy‐inhibiting melittin pro‐peptide (denoted as MEL), which could be triggered by the highly expressed legumain in tumor cells to inhibit the autophagy procedure by disrupting the lysosomal membrane, thus “blocking” the cancer cells from rescuing themselves and amplifying the killing effect of PDT. Both FL and MEL can be specifically activated by TME and the upconversion luminescence imaging of UCNPs offers a tracer function for the treatment. Therefore, UCNPs@FL‐MEL might be an important reference for the design and development of future nanotherapeutic agents.
Mortality Among US Veterans Admitted to Community vs Veterans Health Administration Hospitals for COVID-19
Authors: Michael E. Ohl, Kelly Richardson Miell, Brice F. Beck, Bradley Mecham, George Bailey, Michelle Mengeling, Mary Vaughan-Sarrazin
Journal: JAMA Network Open (2023)

Importance Veterans Health Administration (VHA) enrollees receive care for COVID-19 in both VHA and non-VHA (ie, community) hospitals, but little is known about the frequency or outcomes of care for veterans with COVID-19 in VHA vs community hospitals. Objective To compare outcomes among veterans admitted for COVID-19 in VHA vs community hospitals. Design, Setting, and Participants This retrospective cohort study used VHA and Medicare data from March 1, 2020, to December 31, 2021, on hospitalizations for COVID-19 in 121 VHA and 4369 community hospitals in the US among a national cohort of veterans (aged ≥65 years) enrolled in both the VHA and Medicare with VHA care in the year prior to hospitalization for COVID-19 based on the primary diagnosis code. Exposure Admission to VHA vs community hospitals. Main Outcomes and Measures The main outcomes were 30-day mortality and 30-day readmission. Inverse probability of treatment weighting was used to balance observable patient characteristics (eg, demographic characteristics, comorbidity, mechanical ventilation on admission, area-level social vulnerability, distance to VHA vs community hospitals, and date of admission) between VHA and community hospitals. Results The cohort included 64 856 veterans (mean [SD] age, 77.6 [8.0] years; 63 562 men [98.0%]) dually enrolled in the VHA and Medicare who were hospitalized for COVID-19. Most (47 821 [73.7%]) were admitted to community hospitals (36 362 [56.1%] admitted to community hospitals via Medicare, 11 459 [17.7%] admitted to community hospitals reimbursed via VHA’s Care in the Community program, and 17 035 [26.3%] admitted to VHA hospitals). Admission to community hospitals was associated with higher unadjusted and risk-adjusted 30-day mortality compared with admission to VHA hospitals (crude mortality, 12 951 of 47 821 [27.1%] vs 3021 of 17 035 [17.7%]; P &amp;amp;lt; .001; risk-adjusted odds ratio, 1.37 [95% CI, 1.21-1.55]; P &amp;amp;lt; .001). Readmission within 30 days was less common after admission to community compared with VHA hospitals (4898 of 38 576 [12.7%] vs 2006 of 14 357 [14.0%]; risk-adjusted hazard ratio, 0.89 [95% CI, 0.86-0.92]; P &amp;amp;lt; .001). Conclusions and Relevance This study found that most hospitalizations for COVID-19 among VHA enrollees aged 65 years or older were in community hospitals and that veterans experienced higher mortality in community hospitals than in VHA hospitals. The VHA must understand the sources of the mortality difference to plan care for VHA enrollees during future COVID-19 surges and the next pandemic.
Factors Associated With Cognitive Improvement After Bariatric Surgery Among Patients With Severe Obesity in the Netherlands
Authors: Debby Vreeken, Florine Seidel, Emma M. Custers, Lisette Olsthoorn, Sophie Cools, Edo O. Aarts, Robert Kleemann, Roy P. C. Kessels, Maximilian Wiesmann, Eric J. Hazebroek, Amanda J. Kiliaan
Journal: JAMA Network Open (2023)

Importance Bariatric surgery–induced weight loss is often associated with improved cognitive function. However, improvement in cognitive function is not always exhibited by all patients, and the mechanisms behind cognitive improvement remain unknown. Objective To investigate the association of changes in adipokines, inflammatory factors, mood, and physical activity with alterations in cognitive function after bariatric surgery among patients with severe obesity. Design, Setting, and Participants This cohort study included 156 patients with severe obesity (body mass index [calculated as weight in kilograms divided by height in meters squared], &amp;amp;gt;35) eligible for Roux-en-Y gastric bypass, aged between 35 and 55 years, who were enrolled in the BARICO (Bariatric Surgery Rijnstate and Radboudumc Neuroimaging and Cognition in Obesity) study between September 1, 2018, and December 31, 2020. Follow-up was completed July 31, 2021; 146 participants completed the 6-month follow-up and were included in the analysis. Intervention Roux-en-Y gastric bypass. Main Outcomes and Measures Overall cognitive performance (based on a 20% change index of the compound z score), inflammatory factors (eg, C-reactive protein and interleukin 6 levels), adipokines (eg, leptin and adiponectin levels), mood (assessed via the Beck Depression Inventory), and physical activity (assessed with the Baecke questionnaire). Results A total of 146 patients (mean [SD] age, 46.1 [5.7] years; 124 women [84.9%]) completed the 6-month follow-up and were included. After bariatric surgery, all plasma levels of inflammatory markers, including C-reactive protein (median change, −0.32 mg/dL [IQR, –0.57 to –0.16 mg/dL]; P &amp;amp;lt; .001) and leptin (median change, −51.5 pg/mL [IQR, –68.0 to –38.4 pg/mL]; P &amp;amp;lt; .001), were lower, whereas adiponectin levels were higher (median change, 0.15 μg/mL [IQR, –0.20 to 0.62 µg/mL]; P &amp;amp;lt; .001), depressive symptoms were (partly) resolved (median change in Beck Depression Inventory score, −3 [IQR, –6 to 0]; P &amp;amp;lt; .001), and physical activity level was higher (mean [SD] change in Baecke score, 0.7 [1.1]; P &amp;amp;lt; .001). Cognitive improvement was observed in 43.8% (57 of 130) of the participants overall. This group had lower C-reactive protein (0.11 vs 0.24 mg/dL; P = .04) and leptin levels (11.8 vs 14.5 pg/mL; P = .04) and fewer depressive symptoms at 6 months (4 vs 5; P = .045) compared with the group of participants who did not show cognitive improvement. Conclusions and Relevance This study suggests that lower C-reactive protein and leptin levels, as well as fewer depressive symptoms, might partly explain the mechanisms behind cognitive improvement after bariatric surgery.
Safety and Efficacy Associated With a Family-Centered Procedural Sedation Protocol for Children With Autism Spectrum Disorder or Developmental Delay
Authors: Cyril Sahyoun, Baruch Krauss, Martina Bevacqua, Artiom Antonsen, Laurent Jardinier, Egidio Barbi
Journal: JAMA Network Open (2023)

This case series describes a family-centered procedural sedation protocol including home desensitization to intranasal drug delivery, environmental modification, and intranasal dexmedetomidine combined with nitrous oxide for children with autism spectrum disorder or developmental delay.